Dopamine is a neuromnediator which is involved in controlling motricity, cognitive functions and moods, and is involved in the compensation circuit. Five types of dopaninergic receptor (D1-D5) have been cloned and their levels of expression and cerebral distributions have been analyzed. Among these five types of receptor, at least two types have isoforms (Proc. Natl. Acad. Sci. USA 1998, 95, 7731). Although pharmacologically different, these five types of dopaminergic receptor have been grouped into two subfamilies: the subfamily D1, which comprises the D1 and D5 receptors, and the subfamily D2 which comprises the D2, D3 and D4 receptors. It is possible to differentiate the pharmacological action of the subfamilies D1 and D2, but it is generally difficult to differentiate the function of the various types within each subfamily.
A dysfunction of dopaminergic transmission is involved in the symptomatology of disorders of the central nervous system such as schizophrenic psychosis (Neuropsychopharmacol. 1988, 1, 179), certain neurodegenerative diseases such as, for example, Parkinson""s disease (Neurodegenerative Diseases; Jolles, G.; Stutzmann, J. M.; Eds; Academic Press, 1994, Chap. 8), depression (J. Clin. Psychiatry, 1998, 59 (Suppl. 5), 60), and dependency on certain substances such as, for example, cocaine, tobacco or alcohol (Cell 1997, 90, 991; Nature 1997, 388, 586).
Thus, for example, antagonists of the D2-type central dopaminergic receptors constitute a conventional and clinically effective approach towards treating the positive symptoms of schizophrenic psychosis. However, most of the compounds with such a mechanism of action also induce adverse side effects such as Parkinson-type symptoms (Pharmacotherapy 1996, 16, 160) and/or neuroendocrine disorders (Acta Psychiatr. Scand. 1989, 352, 24).
Mewshaw et al. (Bioorg. Med. Chem. Lett. 1998, 8, 295) have disclosed phenoxyethylamines of formula: 
in which X represents a hydrogen atom, a hydroxyl group, an amino group or a methanesulfonamide group, Y represents a hydrogen atom or a halogen atom and Ar is a phenyl or 2-thienyl group, as being partial agonists of D2-type receptors.
Patents WO 98/08817, U.S. Pat. No. 5,760,070, WO 98/08843 and WO 98/08819 respectively disclose 4-aminoethoxyindoles and 4-aminoethoxyindolones as being agonists of D2-type dopaminergic receptors or inhibitors of dopamine synthesis and release.
Unangst et al. (J. Med. Chem. 1997, 40, 4026) have disclosed aryloxyalkylamines of formula: 
in which X represents an oxygen or sulfur atom or a CH2 group; R1 is a hydrogen or chlorine atom, a hydroxyl or hydroxymethyl group, a nitro group or a hydroxycarbonyl residue; R2 and R3 represent a hydrogen atom, a halogen atom or a methyl group. These compounds are active on the dopaminergic system, in particular on the D4-type receptors, and are potentially useful for treating schizophrenia.
Patent WO 97/23482 discloses octahydropyrrolo[1,2-a]pyrazines of formula: 
in which X represents, inter alia, a hydrogen atom; m and n=0, 1 or 2 and R1 is an unsubstituted, heterocyclic or non-heterocyclic, polycyclic or non-polycyclic aromatic group. These compounds have affinity for dopaminergic receptors and in particular for the D4-type receptors.
Patents FR 2 702 211, JP 51 048 627, JP 51 052 146, DE 2 450 616 and WO 96/31461 disclose 2-[2-(alkoxy)phenoxy]ethylamine derivatives of formula: 
in which R is a C1-C4 alkyl group and R1 represents a 4-benzenebutyl, 4-piperidinemethyl or 4-benzamidobutyl chain. These compounds are claimed as being ligands of the 5-HT1A sub-type receptors (FR 2 702 211 and WO 96/31461) or hypotensive agents and tranquilizers (JP 51 048 627, JP 51 052 146 and DE 2 450 616).
Patent EP 707 007 discloses arylamines with twofold activity simultaneously antagonist towards D2-type receptors and agonist towards 5-HT1A sub-type receptors, which are useful as antipsychotic agents. The compound EMD-12830 (Drug Data Report 1998, 21) of formula: 
is claimed as an atypical antipsychotic agent (i.e. an agent with less of a propensity to induce Parkinson-type side effects than conventional antipsychotic agents).
Patent DE 2 364 685 discloses phenoxyalkylamines, in particular N-[2-(2-methoxyphenoxy)ethyl]pyrid-3- or 4-ylmethanamine are claimed as hypotensive agents.
Angstein et al. (J. Med. Chem. 1965, 8, 356) have disclosed aryloxyalkylamines which are active on the cardiovascular system. Among the compounds disclosed is N-[2-(2-methoxyphenoxy)ethyl]benzenemethanamine.
Goldenberg et al. (Chim. Ther. 1973, 8, 259) have disclosed, inter alia, N-[2-(2-methoxyphenoxy)ethyl-2-benzofuranmethanamines as agents with peripheral vasodilatatory properties.
4-Methoxy-3-[2-[(phenylmethyl)amino]ethoxy]phenol is disclosed in J. Labelled Compd. Radiopharm. 1993, 33, 1091 and N-[2-(2-methoxyphenoxy)ethyl]furfurylamine is disclosed in FR 1 336 684.
3-(Cyclopentyloxy)benzenemethanamine derivatives of formula: 
in which R represents a hydroxyl or methoxy group and R1 represents an aromatic group or a substituted acyl or thioacyl group, are claimed as phosphodiesterase inhibitors in patents WO 97/46561, WO 95/20578, WO 95/04045, WO 94/02465 and WO 93/15044 or as active agents in the treatment of cardiac insufficiency in U.S. Pat. No. 4,971,959.
Patent WO 92/00968 discloses derivatives of formula: 
in which R represents a C4-C6 cycloalkyl group and X is a hydrogen, fluorine or chlorine atom, are claimed for their activity in controlling disorders dependent on TNF production.
Patent WO 98/01417 discloses aromatic and heteroaromatic compounds of formula: 
in which Ar2 is, inter alia, an aromatic group optionally substituted with a non-cyclic lower alkoxy group. These compounds are claimed as influencing calcium receptors.
The present invention relates to a novel family of compounds which correspond to the general formula (1) 
The compounds of this invention have antidopaminergic activity in particular on the receptors of the subfamily D2. In this respect, the compounds of the invention are useful in the treatment of complaints resulting from dopaminergic hyperactivity, such as schizophrenic symptoms and dependency on certain substances. However, the antagonist activity of the products of the invention on the D2-type receptors is exerted only during a transient dopaminergic hyperstimulation. In the absence of dopaminergic hyperactivity, i.e. when the dopamine concentration varies within proportions that are acceptable for normal functioning of neurones, the compounds of the invention do not induce a dopaminergic hyperactivity. The compounds of the invention are thus useful in the treatment of schizophrenic symptoms and have the advantage of being potentially free of the adverse side effects brought about by excessive blocking of the D2-type receptors, such as Parkinson-type symptoms and/or endocrine disorders, at doses that are therapeutically effective for treating schizophrenic psychosis.
The compounds of the invention thus differ from the derivatives of the prior art in their chemical formula and their mechanism of action.
More specifically, the present invention relates to novel compounds corresponding to the general formula (1): 
in which:
X1 is a hydrogen, chlorine or fluorine atom;
X2 has the same meaning as X1;
R1 represents:
a hydrogen, chlorine or fluorine atom;
a substituent R4, a hydroxyl (OH) group, an alkoxy (OR4) group, an alkylcarbonyloxy (OC(O)R4) group, an alkylcarbonyl (C(O)R4) group, an amino (NH2) group, an alkylamino (NHR4) group, a dialkylamino (N(R4)2) group, a [lacuna] (NHC(O)R4) group or a cyano (CN) group;
R2 is a substituent R4 or an alkoxy (OR4) group;
R3 has the same meaning as R1;
R4 represents:
a linear or branched C1-C5 alkyl radical optionally substituted with 1 or 2 fluorine atoms or a hydroxyl (OH) group and optionally containing a double bond;
a 3-, 4-, 5- or 6-membered cycloalkyl radical optionally substituted with 1 or 2 fluorine atoms and optionally containing a double bond;
Y is an oxygen atom or a fluoromethylene (CHF) or difluoromethylene (CF2) group;
z is a methylene (CH2) group, optionally substituted with 1 or 2 methyl (CH3) or fluoromethyl (CH2F) groups;
A represents:
a 3-, 4-, 5- or 6-membeed cycloalkyl radical or a 7- or 8-membered bicyclic radical optionally containing a double bond, an oxo (xe2x95x90O) function, a hydroxyl (OH) group, a methoxy (OCH3) group or 1 or 2 fluorine atoms;
a 5- or 6-membered non-aromatic heterocyclic group containing one or two hetero atoms chosen from nitrogen, oxygen and sulfur, optionally substituted with an oxo (xe2x95x90O) function, a hydroxyl (OH) group, a methoxy (OCH3) group or 1 or 2 halogen atoms.
The invention also relates to the addition salts and optionally the hydrates of the addition salts of the compounds of general formula (1) with pharmaceutically acceptable mineral acids or organic acids.
A subject of the invention is also pharmaceutical compositions containing, as active principle, at least one of the derivatives of general formula (1) or one of the salts thereof or hydrates of the salts thereof in combination with one or more pharmaceutically acceptable excipients, adjuvants or vehicles. Examples which may be mentioned are inclusion complexes, in particular the inclusion complexes formed by the compounds of the invention with xcex2-cyclodextrins.
The pharmaceutical compositions according to the invention are compositions which may be administered orally, nasally, sublingually, rectally or parenterally. It is generally advantageous to formulate such pharmaceutical compositions in unit dose form. In this case, each dose comprises a predetermined amount of the active principle, combined with the vehicle, excipients and/or adjuvants that are suitable, calculated to obtain a given therapeutic effect. As examples of unit dose forms which may be administered orally, mention may be made of tablets, gel capsules, granules, powders and oral solutions or suspensions.
The formulations that are suitable for the chosen administration form are known and described, for example, in: Remington, The Science and Practice of Pharmacy, 19th Edition, 1995, Mack Publishing Company and may thus be readily prepared by a person skilled in the art.
It is known that the dosage varies from one individual to another, according to the nature and severity of the complaint, the chosen route of administration and the weight, age and sex of the patient, and the effective doses will consequently have to be determined as a function of these parameters by a person specialized in the field. As a guide, the effective doses may range between 0.001 and 100 mg/kg/day.
The compounds of general formula (1) may exist in several tautomeric forms. Although not explicitly reported in the present patent application to simplify the graphical representation of the structural formulae, such tautomeric forms are nevertheless included in the field of application of the invention.
When the compounds of the invention comprise an asymmetric carbon atom, the invention relates both to the racemnic mixtures and to the various enantiomers of the compound under consideration, and also to mixtures thereof in all proportions.
According to one specific characteristic of the present invention, R2 represents an isopropoxy.
According to another specific characteristic of the present invention, Y represents an oxygen atom and Z represents a methylene group.
According to another particular characteristic of the present invention, A is chosen from cyclopentyl, cyclohexyl, 2-cyclohexenyl and bicyclo[2.2.1]hept-5-en-2-yl groups.
The compounds of general formula [lacuna] in which:
Y has the same meaning as above,
z represents a methylene radical optionally substituted with a methyl or fluoromethyl group,
X1, X2, R1, R2, R3, R4 and A have the same meaning as above, may be prepared according to the process described in Scheme A.
Scheme A
The compound of formula (1) is prepared by a conventional reductive amination reaction between the compound of formula (2), in which w represents a hydrogen atom or a methyl or fluoromethyl radical, and the primary amine of formula (3). The expression xe2x80x9ca conventional reductive amination reactionxe2x80x9d means that the compound of formula (2) and the amine (3) are reacted in the suitable solvent and that the mixture of reagents (2) and (3) is then subjected to the reducing agent according to a method that is well known to those skilled in the art.
The compounds of formula (1) are purified according to one or more methods chosen from crystallization and/or liquid-phase chromatography techniques. If so desired, they may then be:
salified using a pharmaceutically acceptable acid;
used in the formation of an inclusion complex.
The process for preparing the primary amines of formula (3) depends on the nature of the substituents X1, R1 and R2 borne by the benzene nucleus.
The derivative of formula (4a), which is a precursor of the primary amine (3), in which:
X1 is a hydrogen, chlorine or fluorine atom,
R1 is a hydrogen or fluorine atom, a formnyl group, a nitro group or an ethoxycarbonyl (C(O)OEt) group,
may be obtained by the process described in Scheme B.
Scheme B
4-Nitrocatechol is regioselectivity alkylated using a 2-balopropane to give the derivative (5-3; R1=NO2) according to an experimental protocol similar to that described in (Org. Prep. Proced. Int. 1992, 23, 753). 2-Hydroxy-3-isopropoxybenzaldehyde (5-2; R1=CHO) is a compound which is known in the chemical literature (Heterocycles 1984, 22 (9), 1995). The preparation of 2-isopropoxy-5-ethoxycarbonylphenol (5-1; R1=CO2Et) is disclosed in EP 579 223. A conventional Williamson reaction (J. Med. Chem. 1989, 32, 105) between the appropriate compounds of formula (5) and 1-bromo-2-chloroethane gives the corresponding chloro ether, which, by reaction with potassium phthalimide (Gabriel synthesis) gives the protected amines of formula (4a) in which R1 is H, CHO, NO2, CO2Et and X1 is a hydrogen atom. Under conditions similar to those used to convert the phenol of formula (5) into the protected amine of formula (4a), 5-fluoro-2-hydroxyacetophenone is converted into the protected amine of formula (7; R=CH2CH2NPht). A Bayer-Villiger reaction carried out on the compound of formula (7), Synth. Commun 1989, 11/12, 2001, followed by a basic hydrolysis reaction of the intermediate formate gives the phenol of formula (6; R=CH2CH2NPht). Alkylation of the phenol of formula (6) under the usual conditions gives the compound of formula (4a) in which R1 is a fluorine or chlorine atom and X1 is a hydrogen atom. Inversion of the order of incorporation of the alkyl residues on the intermediates of formulae (7) and (6) gives access, under experimental conditions identical to those described above, to the compounds of formula (4a) in which R1 is a hydrogen atom and X1 is a fluorine or chlorine atom.
The amine derivatives of formula (4b-f), which are precursors of the primary amiines (3), in which:
X1 is a hydrogen atom,
R1 is a group R4, C(O)R4, OH or OR4,
may be obtained according to the process described in Scheme C.
Scheme C
The compound of formula (4a-2) is the intermediate used to prepare the protected arnines of formulae (4b-g).
According to route a: a conventional Wittig reaction between the intermediate of formula (4a-2) and methyltnphenylphosphonium iodide gives the vinyl derivative of formula (4b). The derivative of formula (4b) may:
either be used directly in the preparation of the compounds of formula (1) in which R4 is a vinyl group;
or be reduced, under conventional hydrogenation conditions catalyzed with transition metals, to give the compound of formula (4c);
or be oxidized, according to a conventional Wacker reaction (Org. Synth. 1988, 67, 12) to give the compound of formula (4d). A process similar to the process described by route a may then be repeated using the ketone (4d) to give the compound of formula (4e).
The use of a non-stabilized phosphonium ylid, derived from a higher alkane halide, gives access to the derivatives of formula (4b-e) in which R1 represents a group R4 or C(O)R4 other than a methyl group.
The ketone function of the derivative of formula (4d) may also be reduced to a secondary alcohol function such as, for example, that present in compound 4h.
According to route b: a Bayer-Villiger reaction, under conditions identical to those described for the preparation of the phenol of formula (6) from the intermediate of formula (7), Scheme B, gives the phenol of formula (4f) which may then be alkylated, under the usual conditions, to give the derivatives of formula (4g).
The derivatives of formula (4i), which are precursors of the primary amines (3), in which:
X1 is a hydrogen atom,
R1 is a group NH2, NHR4, N(R4)2 or NHC(O)R4,
are obtained according to the process described in Scheme D.
Scheme D
The intermediate of formula (4a-6) is prepared by means of a Mitsunobu reaction between the compound of formula (5; R1=NO2, Scheme A) and tert-butyl (2-hydroxyethyl)carbamate (Eur. J. Med. Chem. 1995, 30, 387). Reduction of the nitro function of the compound of formula (4a-6), J. Org. Chem. 1987, 52, 1844, gives the amine of formula (4g-2). Acylation of the amine of formula (4g-2), under conventional experimental conditions, gives the derivative of formula (4i) in which R1 is a group (R4CONH). The derivatives of formula (4i) in which R1 represents a group NHR4 or N(R4)2 are readily prepared from the compound of formula (4g-2) by means of reactions that are well known to those skilled in the art.
The compounds of formula (4j) or (4k) in which: 
X1, R1 and R4 have the same meaning as above, are prepared according to processes similar to those described for the preparation of the compounds of formula (4a-i) from suitably substituted phenols, which are commercially available or prepared according to methods known in the chemical literature.
The primary amines of formula (3), prepared by deprotection of the compounds of formula (4a-i), are used immediately in the following reductive amination step (Scheme A). The methods for deprotecting the amines of formulae (4a-i) are described in Scheme E.
Scheme E
Deprotection of the compounds of formula (4a-h) is carried out by moderate heating (60xc2x0 C.) of the derivatives of formula (4a-h) in the presence of an excess of 2-aminoethanol (route a). Deprotection of the compounds of formula (4i) is carried out by treating a solution of compounds (4i) in dichloromethane with an excess of trifluoroacetic acid (route b).
The process for preparing the aldehydes of formula (2), Scheme A, depends on the nature of the substituent R3.
The aldehydes of formula (2a) in which:
R3 is a hydrogen atom or an OCH3 group,
A has the same meaning as above,
are prepared by the process described in Scheme F.
Scheme F
3-Hydroxybenzaldehyde or 2-methoxy-5-hydroxybenzaldehyde, prepared according to J. Org. Chem. 1974, 39, 2437, is alkylated using the appropriate cycloalkane halide or cycloalkene halide, under conditions that are identical to those described above for the formation of the ether of formula (5) from 4-nitrocatechol (Scheme B), to give the compounds of formula (2a) in which R3 is a hydrogen atom or a methoxy group. However, when A represents a bicyclic group, for example a bicyclo[2.2.1]hept-5-ene group, the etherification reaction under consideration is preferably accomplished using the appropriate bicyclic alcohol by means of a Mitsunobu reaction according to a procedure which is identical to the one described in (J. Med. Chem. 1991, 34, 291).
The aldehydes of formulae (2b) in which:
R3 is a fluorine atom or a chlorine atom,
A has the same meaning as above,
are prepared by the process described in Scheme G.
Scheme G
The appropriate 3-methyl-4-halophenol (R3=Cl or F) is alkylated under conditions identical to those used for the preparation of the compound of formula (2a) from the corresponding phenol (Scheme F). The compound of formula (8) is then selectively brominated on the methyl group in the benzylic position (J. Med. Chem. 1982, 25, 1204) to give the compound of formula (9) which is oxidized to the aldehyde of formula (2b) according to the method developed by Kornblum (J. Org. Chem. 1986, 51, 1264).
The aldehydes of formula (2c) in which:
X2 is a fluorine or chlorine atom,
A has the same meaning as above,
may be prepared according to a method which is identical to the one disclosed in WO 92/00968.
The compounds of formulae (4a-i) and (2a-c) constitute the set of compounds of formulae (4) and (2). 